US6828297B2ExpiredUtilityA1

Mixtures of insulin drug-oligomer conjugates comprising polyalkylene glycol, uses thereof, and methods of making same

Assignee: NOBEX CORPPriority: Jun 4, 2001Filed: Jun 4, 2001Granted: Dec 7, 2004

Est. expiryJun 4, 2021(expired)· nominal 20-yr term from priority

Inventors:Nnochiri Ekwuribe Christopher H. Price Aslam M. Ansari Balasingam Radhakrishnan Amy L. Odenbaugh

A61K 47/60A61K 45/06A61P 3/10A61P 5/50A61K 38/28

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Claims

Abstract

A mixture of conjugates in which each conjugate in the mixture comprises an insulin drug coupled to an oligomer that includes a polyalkylene glycol moiety is disclosed. The mixture may exhibit higher in vivo activity than a polydispersed mixture of similar conjugates. The mixture may also be more effective at surviving an in vitro model of intestinal digestion than polydispersed mixtures of similar conjugates. The mixture may also result in less inter-subject variability than polydispersed mixtures of similar conjugates.

Claims

exact text as granted — not AI-modified

What is claimed is:

1. A mixture of conjugates, each comprising human insulin coupled to an oligomer that comprises a polyethylene glycol moiety, wherein the mixture has a dispersity coefficient (DC) greater than 10,000 where DC = ( ∑ i = 1 n  N i  M i ) 2 ∑ i = 1 n  N i  M i 2  ∑ i = 1 n  N i - ( ∑ i = 1 n  N i  M i ) 2
wherein:
n is the number of different molecules in the sample;
N i is the number of i th molecules in the sample; and
M i is the mass of the i th molecule; and
wherein the conjugate comprises a first oligomer and a second oligomer; and
wherein the first oligomer is covalently coupled at Lys B29 of the insulin and the second oligomer is covalently coupled at N-terminal A1 or N-terminal B1 of the insulin.

2. The mixture according to claim 1 , wherein the insulin is covalently coupled to at least one of the oligomers by a hydrolyzable bond.

3. The mixture according to claim 1 , wherein the insulin is covalently coupled to the polyethylene glycol moiety of at least one of the oligomers.

4. The mixture according to claim 1 , wherein at least one the oligomers further comprises a lipophilic moiety covalently coupled to the polyethylene glycol moiety.

5. The mixture according to claim 1 , wherein at least one of the oligomers further comprises a lipophilic moiety.

6. The mixture according to claim 5 , wherein the insulin is covalently coupled to the lipophilic moiety.

7. The mixture according to claim 5 , wherein the polyethylene glycol moiety is covalently coupled to the lipophilic moiety.

8. A mixture of conjugates, each comprising an insulin drug coupled to an oligomer having a formula:
wherein the mixture has a dispersity coefficient (DC) greater than 10,000, where DC = ( ∑ i = 1 n  N i  M i ) 2 ∑ i = 1 n  N i  M i 2  ∑ i = 1 n  N i - ( ∑ i = 1 n  N i  M i ) 2
wherein:
n is the number of different molecules in the sample;
N i is the number of i th molecules in the sample;
M i is the mass of the i th molecule; and
the conjugate comprises a first oligomer and a second oligomer.

9. The mixture according to claim 1 , wherein the first and the second oligomers are the same.

10. The mixture according to claim 1 , wherein at least one of the oligomers comprises a first polyethylene glycol moiety covalently coupled to the insulin by a non-hydrolyzable bond and a second polyethylene glycol moiety covalently coupled to the first polyethylene glycol moiety by a hydrolyzable bond.

11. The mixture according to claim 10 , wherein the oligomer(s) comprising a polyethylene glycol moiety covalently coupled to the insulin by a non-hydrolyzable bond and a second polyethylene glycol moiety covalently coupled to the first polyethylene glycol moiety by a hydrolyzable bond further comprises a lipophilic moiety covalently coupled to the second polyethylene glycol moiety.

12. The mixture according to claim 1 , wherein each of the conjugates is amphiphilically balanced such that each conjugate is aqueously soluble and able to penetrate biological membranes.

13. The mixture according to claim 1 , wherein at least one of the oligomers comprises a polyethylene glycol moiety having at least 2 polyethylene glycol subunits.

14. The mixture according to claim 1 , wherein at least one of the oligomers comprises a polyethylene glycol moiety having at least 5 polyethylene glycol subunits.

15. The mixture according to claim 1 , wherein at least one of the oligomers comprises a polyethylene glycol moiety having at least 7 polyethylene glycol subunits.

16. The mixture according to claim 1 ,wherein the first oligomer has the formula:

17. A substantially monodispersed mixture of conjugates, each comprising human insulin coupled to an oligomer that comprises a polyethylene glycol moiety,
wherein the conjugate comprises a first oligomer and a second oligomer; and
wherein the first oligomer is covalently coupled at Lys B29 of the insulin and the second oligomer is covalently coupled at N-terminal A1 or N-terminal B1 of the insulin.

18. The mixture according to claim 17 , wherein the insulin is covalently coupled to at least one of the oligomers by a hydrolyzable bond.

19. The mixture according to claim 17 , wherein the insulin is covalently coupled to the polyethylene glycol moiety of at least one of the oligomers.

20. The mixture according to claim 17 , wherein at least one of the oligomers comprises a lipophilic moiety covalently coupled to the polyethylene glycol moiety.

21. The mixture according to claim 17 , wherein at least one of the oligomers comprises a lipophilic moiety.

22. The mixture according to claim 21 , wherein the insulin is covalently coupled to the lipophilic moiety.

23. The mixture according to claim 21 , wherein the polyethylene glycol moiety is covalently coupled to the lipophilic moiety.

24. A substantially monodispersed mixture of conjugates, each comprising an insulin drug coupled to an oligomer having a formula:
wherein the conjugate comprises a first oligomer and a second oligomer.

25. The mixture according to claim 17 , wherein the first and the second oligomers are the same.

26. The mixture according to claim 17 , wherein the mixture is monodispersed.

27. The mixture according to claim 17 , wherein at least one of the oligomers comprises a first polyethylene glycol moiety covalently coupled to the insulin by a non-hydrolyzable bond and a second polyethylene glycol moiety covalently coupled to the first polyethylene glycol moiety by a hydrolyzable bond.

28. The mixture according to claim 27 , wherein the oligomer(s) comprising a first polyethylene glycol moiety covalently coupled to the insulin by a non-hydrolyzable bond and a second polyethylene glycol moiety covalently coupled to the first polyethylene glycol moiety by a hydrolyzable bond further comprise a lipophilic moiety covalently coupled to the second polyethylene glycol moiety.

29. The mixture according to claim 17 , wherein each of the conjugates is amphiphilically balanced such that each conjugate is aqueously soluble and able to penetrate biological membranes.

30. The mixture according to claim 17 , wherein at least one of the oligomers comprises a polyethylene glycol moiety having at least 2 polyethylene glycol subunits.

31. The mixture according to claim 17 , wherein at least one of the oligomers comprises a polyethylene glycol moiety having at least 5 polyethylene glycol subunits.

32. The mixture according to claim 17 , wherein at least one of the oligomers comprises a polyethylene glycol moiety having at least 7 polyethylene glycol subunits.

33. The mixture according to claim 17 , wherein the first oligomer has the formula:

34. The mixture according to claim 8 , wherein the dispersity coefficient is greater than 100,000.

35. The mixture according to claim 8 , wherein the dispersity coefficient is greater than 500,000.

36. The mixture according to claim 8 , wherein the insulin drug is human insulin and the oligomer is covalently coupled to Lys B29 of the human insulin.

37. The mixture according to claim 8 , wherein the mixture has an in vivo activity that is greater than the in vivo activity of a polydispersed mixture of insulin drug-oligomer conjugates having the same number average molecular weight as the mixture.

38. The mixture according to claim 8 , wherein the mixture has an in vitro activity that is greater than the in vitro activity of a polydispersed mixture of insulin drug-oligomer conjugates having the same number average molecular weight as the mixture.

39. The mixture according to claim 8 , wherein the insulin-drug oligomer has an increased resistance to degradation by chymotrypsin when compared to the resistance to degradation by chymotrypsin of a polydispersed mixture of insulin drug-oligomer conjugates having the same number average molecular weight as the mixture.

40. The mixture according to claim 8 , wherein the mixture has an inter-subject variability that is less than the inter-subject variability of a polydispersed mixture of insulin drug-oligomer conjugates having the same number average molecular weight as the mixture.

41. The mixture according to claim 24 , wherein the mixture is monodispersed.

42. The mixture according to claim 24 , wherein the insulin drug is human insulin and the oligomer is covalently coupled to Lys B29 of the human insulin.

43. The mixture according to claim 24 , wherein the mixture has an in vivo activity that is greater than the in vivo activity of a polydispersed mixture of insulin drug-oligomer conjugates having the same number average molecular weight as the mixture.

44. The mixture according to claim 24 , wherein the mixture has an in vitro activity that is greater than the in vitro activity of a polydispersed mixture of insulin drug-oligomer conjugates having the same number average molecular weight as the mixture.

45. The mixture according to claim 24 , wherein the insulin-drug oligomer has an increased resistance to degradation by chymotrypsin when compared to the resistance to degradation by chymotrypsin of a polydispersed mixture of insulin drug-oligomer conjugates having the same number average molecular weight as the mixture.

46. The mixture according to claim 24 , wherein the mixture has an inter-subject variability that is less than the inter-subject variability of a polydispersed mixture of insulin drug-oligomer conjugates having the same number average molecular weight as the mixture.

47. The mixture according to claim 24 , wherein the insulin drug is covalently coupled to the oligomer.

48. A composition comprising:
the mixture according to claim 1 ; and
a pharmaceutically acceptable carrier.

49. A method of treating insulin deficiency in a subject in need of such treatment, said method comprising administering an effective amount of a mixture of conjugates according to claim 1 .

50. A composition comprising:
the mixture according to claim 8 ; and
a pharmaceutically acceptable carrier.

51. A method of treating insulin deficiency in a subject in need of such treatment, said method comprising administering an effective amount of a mixture of conjugates according to claim 8 .

52. A composition comprising:
the mixture according to claim 24 ; and
a pharmaceutically acceptable carrier.

53. A method of treating insulin deficiency in a subject in need of such treatment, said method comprising administering an effective amount of a substantially monodispersed mixture of conjugates according to claim 24 .

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